Deciphering the Role of Cancer Stem Cells in Chemotherapy Resistance in High-Grade Serous Carcinoma
Abstract
The human body is composed of an estimated 37 trillion cells that live harmoniously among their neighbors. An equilibrium between differentiated cells, progenitor cells, and stem cells has to be achieved at any point of development to enable homeostasis and proper tissue organization. However, in cancer, a single cell can lead to the downfall of an entire organism. To ensure that all the signals and processes are coordinated, cells need to regulate the expression of genes using a multitude of factors (transcription factors that bind to the DNA itself) and chromatin regulators (proteins that surround the DNA). In cancer, there is growing evidence that a small pool of cells may be responsible for metastasis, drug resistance, and ultimately tumor relapse. Such cells can be identified as cancer stem cells and may be regulated by specific transcription factors that drive a more resilient tumor. In High Grade Serous Carcinoma, the most lethal subtype of ovarian cancer, response to platinum-based chemotherapy agents has been the most critical indicator of a good prognosis since other options are very limited. In this project, we aim to identify and characterize the pool of cancer stem cells that may be responsible for drug resistance. The hypothesis is that platinum resistance is driven by a stem cell signature that is associated with cell survival and proliferation. We will be using novel sequencing techniques to profile single cells, which will help us characterizing the tumor heterogeneity, identifying cancer stem cells, and understanding how they are regulated. We will also be performing the characterization of the stem cell pool through induction of platinum resistance in patient-derived tumor models, akin to the actual clinical setting. Finally, we will be developing new tools to identify the cancer stem cells in the context of their natural microenvironment, which we can then use to more efficiently test different combinations of possible therapies. Since establishing my laboratory at Mayo Clinic, my group has been working on various aspects of transcription and enhancer regulation with implications in cellular heterogeneity and drug resistance in cancer. Without any experience in ovarian cancer prior to my position at Mayo, I decided to focus on ovarian cancer with full support of my department, the Mayo Clinic ovarian cancer SPORE, and the ovarian cancer research groups at Mayo Clinic. For the Early-Career Investigator at the Ovarian Cancer Academy (OCA), I designated two mentors with great ovarian cancer experience to help me progress in my career: Dr. Fergus Couch and Dr. John Weroha. Being a part of the Academy will significantly enhance the quality of my research through greater exposure to external resources and novel collaborations. My laboratory is exploring the great potential of understanding drug resistance in ovarian cancer through the lens of epigenetic deregulation of cancer stem cells using three complementary avenues: (1) technology development (single cell profiling), (2) bioinformatic analysis of different sequencing modalities, and (3) mechanistic studies that include the understanding of cancer stem cells in the context of the microenvironment. I also have unprecedented access to a variety of tumor models of ovarian cancer, bioengineering collaborators to develop 3D co-culturing systems, and full support of a gynecological surgical team to obtain human tissue for translationally relevant research. My experience in stem cell biology and cancer epigenetics will be critical for the success of this project and to establish myself in ovarian cancer research. I am fully committed to participating in the OCA. If selected, I will use this incredible opportunity to broaden and diversify my experience on methods to understand the interplay between the microenvironment and role in cancer stem cells. I also believe that my epigenomic expertise and stem cell background will be of great valu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110475
Entities
People
- Alexandre Maia
Organizations
- Mayo Clinic
- United States Army