A diverse collection of laboratory-based research efforts generates robust data supporting everything from new drug targets to improved risk screening for diverse populations.
The breadth and richness of basic science research underway at Cedars-Sinai Cancer has wide-ranging implications that alter the approach to cancer care—and future research—here and around the world. As our oncologists, the National Cancer Institute, and our own Community Outreach and Engagement team identify gaps in cancer knowledge, our research scientists pivot to skillfully address the field’s most pressing questions.
With translation and impact top of mind, our laboratory experts work to reduce disparities in health outcomes and improve survival rates for patients with some of the most overlooked, aggressive and treatment-resistant cancers.
Understanding Breast Cancer in Transgender Men
L.A. County is home to the second-largest and the most racially and ethnically diverse LGBTQIA+ community in the nation. With the National Cancer Institute’s identification of sex as a critical biological variable for cancer research as well as a push toward improving healthcare for historically marginalized populations, Cedars-Sinai investigators are striving to better understand the impact of sex and gender on cancer biology.
Our scientists have worked to define the impact of androgen therapy on breast cells and cancer risk, creating the first map of transcriptional signatures of each cell type in the breasts of transgender men.1 Single-cell-resolution transcriptome, chromatin and spatial profiling of breast tissues from transgender men following androgen therapy found canonical androgen receptor gene target upregulation in cells expressing the androgen receptor. These methods also found that paracrine signaling drives sex-specific androgenic effects in other cell types, as well as a spatial reconfiguration of immune, fibroblast and vascular cells.
This work elucidates the molecular consequences of androgen activity in the human breast at single-cell resolution for the first time. The findings also reveal a potential therapeutic strategy: using androgen therapy to prevent or treat estrogen receptor-positive breast cancer.
Groundbreaking “Loss of Y” Findings in Bladder Cancer
In a longstanding effort to understand the role of sex as a biological variable in cancer development and aggressiveness, researchers at Cedars-Sinai Cancer have transformed the field’s perception of the Y chromosome.2 As men age, some of their cells lose the Y chromosome entirely.
Traditionally thought to determine nothing more than biological sex, loss of the Y chromosome has been increasingly implicated in the presence and progression of various cancers, including up to 40% of bladder cancers.
Cedars-Sinai Cancer investigators found “loss of Y” or LOY-driven tumors better evade the adaptive immune system by exhausting T-cells. This lowers the body’s natural ability to fend off cancer, resulting in more aggressive disease. On the flip side, these tumors are also more vulnerable to immune checkpoint inhibitors.
Now, the research team has begun exploring the potential of LOY to serve as a biomarker for cancer aggressiveness and susceptibility to checkpoint inhibitors for males with bladder cancer. The team believes Y chromosome gene counterparts on the X chromosome, called paralog genes, could also hold valuable insights into sex differences in cancers and treatment response.
Induced Pluripotent Stem Cells and Organoids Shed Light on Ovarian Cancer
Cedars-Sinai researchers uncovered a novel origin point for aggressive ovarian cancer, which offers opportunities for early detection and improved personalized therapeutics. The cross-disciplinary project, published in Cell Reports,3 compared cancer models generated from healthy young women and those with early-onset ovarian cancer with the BRCA1 mutation—a trait associated with significantly increased risk for high-grade serous cancer in the breasts, ovaries and fallopian tubes.
Using patient blood samples, the team generated induced pluripotent stem cells (iPSCs) to form the foundation for fallopian tube organoids. These tissue models offered insights into the development of cellular pathologies and the differences between healthy individuals and those with the BRCA1 mutation.
Our collaborative teams have begun searching for novel clinical biomarkers for risk prediction, early-stage disease screening, and preventive and therapeutic targets for ovarian cancer. Investigators are also applying iPSC technology interprogrammatically to studies in breast, pancreas and prostate cancers with the goal of making similar discoveries in these challenging diseases.
Changing the Future for Men With Metastatic Prostate Cancer
Men with metastatic prostate cancer have notoriously poor outcomes when androgen manipulation fails. That’s why our scientists studied human high-dimensional patient data to identify molecular processes at work in the highest-risk cases.
Their studies uncovered a key mechanism: Increased activity of the transcription factor ONECUT2 (OC2) triggers a signaling program that drives metastatic castration-resistant prostate cancer (mCRPC). Moving these findings to mouse models of metastatic disease revealed that OC2 silencing inhibits prostate cancer growth and metastasis. The team also developed a family of specific OC2 inhibitors. Gene expression analysis of data obtained from patients showed an association between elevated OC2 expression and prostate tumor recurrence, supporting OC2’s role as a master regulator of mCRPC and implicating it as a potential diagnostic and therapeutic target for this challenging disease.4
Additional prostate cancer studies identified a protein known as receptor-interacting protein kinase 2—or RIPK2—as another disease promoter present in increasing amounts as cancer progresses.5
Initial CRISPR/Cas9 gene-editing studies found that targeting RIPK2 with ponatinib, an existing FDA-approved protein inhibitor, reduced prostate cancer metastasis by 92% in mice.
The Best of Both Worlds
The basic science initiatives led by the researchers, clinician-scientists and multidisciplinary experts at Cedars-Sinai Cancer connect under an overarching goal to eliminate cancer. This work advances novel scientific aims as well as time-sensitive queries with promise for imminent translation to the clinic. The result: a bevy of projects shaping medical science and medical treatment at Cedars-Sinai and beyond.
“The molecular consequences of androgen activity in the human breast.” Cell Genom. PMID: 36950379.
“Y chromosome loss in cancer drives growth by evasion of adaptive immunity.” Nature. PMID: 37344596