The preclinical study was published in Cell Reports Medicine. 

“Our study is the first to show how metabolites produced by select bacteria can induce changes in the body’s immune response when the body is fighting cancer,” said Ze’ev Ronai, PhD, director of the Translational Research Institute at Cedars-Sinai, professor of Surgery and senior author of the study. “Previous research established that gut bacteria affect the immune system and can help fight cancer. Our new findings are an important step forward because they give us a specific metabolite that can be used for future therapies.” 

The investigators focused on B. rodentium in the guts of mice and a related bacteria species, B. uniformis, in the guts of humans. When these bacteria break down the amino acid tryptophan, they produce different forms of metabolites called indoles. 

In laboratory mice, investigators found that treatment with B. rodentium restricted the growth of melanoma and colon, breast and pancreatic cancers, and that treatment with indole on its own restricted the growth of melanoma.

“Indole was more effective against these tumors than other metabolites produced by tryptophan breakdown, which are used in immunotherapies,” said Ximena Diaz Olea, a research scientist in the Ronai Lab and first author of the study. 

The investigators also looked at data from human patients who were responding well to immunotherapy for melanoma. In these patients, investigators found increased levels of the enzymes used to produce indole, suggesting higher levels of indoles were contributing to the patients’ good outcomes. 

“We are now evaluating whether increasing the levels of indoles in the gut would be sufficient to inhibit cancer,” Ronai said. “We hope to turn these findings into a therapy that will benefit patients.”

Investigators say this might be possible by giving patients capsules containing B. uniformis, then following up with nutrients to increase the bacteria’s reproduction and indole levels in the gut.

While this study focused on B. uniformis and B. rodentium, as many as 20 different bacteria species produce the enzyme that creates indole, opening further avenues for exploration, Ronai said. 

“These findings provide the foundation for modes of treatment that could complement or replace existing ones,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “This type of translational science paves the way toward new options for patients.” 

If investigators are successful at translating their findings into an anticancer therapy, Ronai said that it would likely be useful against many cancer types, as the immune cells bolstered by indole are effective against many cancers.

Additional Cedars-Sinai authors include Ximena Diaz Olea, Aagam Shah, Hyungsoo Kim, Ashok Kumar Sharma, Anthony Martin, Mark B. Faries, Omid Hamid, Suzanne Devkota, and Simon Knott.

Other authors include Kristin Beede, Gabriel Pereira, David Scott, Christopher Petucci, Eric Martens, Dmitri Rodionov, Miguel P. Martinez, Tongwu Zhang, Andrei Osterman, Emile E. Voest, Nadim J. Ajami, Jennifer Wargo, and Amanda E. Ramer-Tait.

Funding: This work was supported by the Cedars-Sinai shared resources in genomics, vivarium and microbiome studies; NCI grant R35CA197465 (to ZAR); the Hervey Family / San Diego Foundation (to ZAR); grant R21CA249822 (to ART and HK); and the Buffett Cancer Center funds (to ART) via NCI grant CA036727.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

According to Nima Gharavi, MD, PhD, chief of the Department of Dermatology at Cedars-Sinai, too much exposure to ultraviolet rays, or UV rays, can increase your risk for melanoma—a type of aggressive skin cancer.

“With every sunburn, the risk for melanoma increases slightly,” said Gharavi, who also serves as the director of Dermatologic Surgery and Mohs Micrographic Surgery and associate clinical professor of Medicine and Pathology.

Gharavi recently spoke with Cedars-Sinai Newsroom on how to spot melanoma, treatment options and steps you can take to lower your risk of skin cancer. 

What is melanoma?

Melanoma is cancer that arises from the melanocyte, which is the cell type that makes up moles and pigments that give skin its color.

What are the signs and symptoms of melanoma?

The most important clue is a mole that's changing. One of the criteria we typically follow is called the ABCDE of melanoma.

• A stands for Asymmetry. Moles are asymmetric if one half doesn't equal the other half.
• B is for the Borders. Are the borders irregular?
• C is for Color. If there are multiple colors within a mole, get it checked.
• D is Diameter. If the mole is bigger than six millimeters, which is about the size of a pencil eraser, it should be evaluated.
• E is for Evolving. Has the mole evolved or changed recently?

How do you diagnose melanoma?

Some patients, when they notice something suspicious, will present it to the primary care doctor, who will then refer the patient to a dermatologist. Others may present directly to the dermatologist.

A dermatologist would look at the mole and see if there's anything clinically suspicious about it. If it meets clinical criteria for a biopsy, a biopsy would be performed to rule out atypical features and to rule out melanoma.

Based on the biopsy, it'll tell us not only the diagnosis, but also what type of melanoma the patient has. And more importantly, you get some information about how deep the melanoma has spread into the skin. That information is probably the most important because it determines what stage of cancer the patient has.

Who’s at risk for melanoma?

Melanoma can affect every skin type. That being said, there are certain people who have a higher risk for developing melanoma. Patients who have light skin, light eyes or red hair are at a higher risk.

Patients who have a previous history of skin cancer or a family history of skin cancer, including melanoma, are at higher risk. Genetics obviously plays an important role.

Some patients also have a large number of moles on their body. So, if you have a lot of larger abnormal-looking moles, then usually there's a higher risk associated with that as well. Lastly, patients who have either had a lot of sun exposure throughout their life or use or have used indoor tanning in the past are at higher risk for melanoma.

How do you treat melanoma?

If a patient is diagnosed with early-stage melanoma, the treatment is surgery and surgery alone. The amount of skin that's removed is also determined by how deep that melanoma has spread into the skin. Surgery is typically performed by either a dermatologist/dermatologic surgeon or a surgical oncologist. As melanoma starts spreading deeper into the skin, patients might be candidates for other options.

For aggressive cases that are stage 3 and beyond, using systemic medications like immunotherapy—medications that activate the immune system to fight off any remaining melanoma cells that may be circulating through the bloodstream—seems to be the best option.

What is Mohs micrographic surgery?

Mohs micrographic surgery (MMS) is an option for a subtype of melanomas—those that are predominantly on the head and neck or on other cosmetically sensitive areas with extensive sun damage. So, typically we're talking about melanomas on the scalp, forehead, cheeks, nose or ear.

With MMS, the surgeon is the pathologist, and the lab is right there in the office. This allows the surgeon to perform the examination in real time. So, what you do is you surgically remove the melanoma tissue along with a small border of healthy tissue and send it to the lab for processing slides. The lab processes it within 45 minutes and sends the slides back to the surgeon. The surgeon looks at the tissue under the microscope and determines if the border that was removed is free of melanoma. The advantage of that is you get the results a lot quicker. The other advantage is, if you need to do more surgery, you can do it right away. You don't have to bring the patient back in two to three days later. Lastly, MMS allows for a high level of precision when removing skin cancer, which leads to superior cure rates for these types of melanomas.

Can you prevent melanoma?

There are a few things that we can do to minimize the risk of getting melanoma. No. 1 is to avoid the sun during peak hours, which are typically between 10 a.m. and 2 p.m.

If you're going to be out during the peak hours, seek shade. If you can, wear sun-protective clothing, such as long sleeves and pants. There is also clothing out there with a UV protective factor. Also, wear hats, ideally a wide-brimmed hat that covers the ears as well. Lastly, wear sunscreen. The recommendation is at least SPF 30 or higher.

If you do have a history of sun damage or skin cancer or a personal or family history of melanoma, then visiting a dermatologist routinely for skin checks is invaluable because the sooner we can diagnose melanoma, the treatments afterwards might be less debilitating.

One of the things we tell patients to do is do skin checks at home. When you're in the shower, maybe once a month, just take a look at the skin, look at any moles, see if anything looks out of the ordinary. You can take a picture of it with your phone or have your significant other or family member take a picture of it. And then maybe a month later, take another picture and compare the pictures and see if there is any noticeable change.

Read more on the Cedars-Sinai Blog: Dermatology for Skin of Color

for patients, caregivers and clinicians. Melanoma, which originates in the skin’s pigment-producing cells, accounts for only 1% of skin cancers but is responsible for most skin cancer deaths.

“In our 14th year hosting this symposium, we remain fully committed to our role as one of the largest melanoma treatment centers in the U.S.,” said Lawrence Piro, MD, president and CEO of the institute. “Continually educating melanoma clinicians, patients and survivors is an essential part of that role.”

The symposium will take place from 9 a.m.-noon Saturday, May 11, at The Angeles Clinic and Research Institute and online. Topics will include immunotherapy, cellular therapy, radiation therapy, clinical trials, survivorship, and advances against less common forms of melanoma.

“Each presentation is a conversation between our experts and the community of patients, caregivers, and physicians,” said Omid Hamid, MD, chief of Translational Research and Therapy and director of Melanoma Therapeutics.

Hamid and Mark Faries, MD, head of Surgical Oncology and co-director of the Melanoma Program, sat down with the Cedars-Sinai Newsroom to discuss advances in melanoma patient care.

How has melanoma treatment changed over the past decade or so?

Hamid: When we began hosting these events, there were virtually no approved treatments for melanoma. Over the course of these last 14 or 15 years, we’ve seen the development of many therapies, including bispecifics (a type of antibody) and cellular therapies. We're now looking not just to improve outcomes in cutaneous melanoma, the most common type, but to improve outcomes for other melanomas as well.

Faries: The advances that we've seen in systemic therapies have also allowed us to be more selective and targeted, and less invasive, with the surgical approaches that we use. Surgical procedures still have an important role in treatment, but we're able to use more discretion about the sorts of surgeries we employ.

How do cellular therapies work?

Faries: T cells, which are part of the body’s immune system, recognize melanoma as abnormal and attack it. Sometimes, however, the response is not adequate and the cancer spreads. We can remove one of the patient’s tumors and put that tissue into culture to allow the T cells in the tumor to become stronger and grow. Then we expand those cells to enormous numbers and give them back to the patient to shift the balance of power, so that the T cells have the upper hand.

What clinical trial options are available for melanoma patients?

Hamid: We have a multitude of clinical trials available. These include trials of cellular therapies, bispecific antibodies that recruit immune cells to attack tumors, and oncolytic viruses that can infect and kill cancer cells—including some that can be given intravenously to reach tumors that we cannot reach directly with an injection.

Faries: One of our goals is to have clinical trial options available to patients at every stage of their disease and treatment that build on the advances of recent years. Across all points along the patient’s journey, there are clinical trial options that give them opportunities that they might not have otherwise.

How has survivorship for melanoma patients evolved?

Hamid: Survivorship services are more important than ever as we see patients with metastatic melanoma surviving years and decades, some continuing treatment and some cleared of their cancer. Survivorship is not only living longer, but also living better. It's learning to cope with issues like long-term toxicities that can come from therapy, survivor's guilt, how to become involved in care, and getting involved in giving back to this community as a survivor. Many of the therapies leading to improved survival have originated here at The Angeles Clinic and Research Institute, and our symposium will provide a wealth of information about the programs and services available to support melanoma survivors.

Learn more about The Angeles Clinic and Research Institute on X at @angelesclinic.

Read more on the Cedars-Sinai Blog: A Lifesaving Second Opinion for Melanoma