Research Fellow-Sethi Lab

Cancer-causing mutations alone do not determine whether a cell becomes malignant. Cells must also acquire abnormal identities - and retain the ability to change state during cancer progression and therapy.

The Sethi Laboratory at Dana-Farber Cancer Institute and Harvard Medical School is recruiting an exceptional experimental postdoctoral fellow with expertise in molecular biology, biochemistry, chromatin biology, or cancer

cell biology to investigate the molecular machinery controlling these transitions.

Our laboratory seeks to understand how pathologic cell states are created, how they become durably encoded, and how they can ultimately be erased or therapeutically targeted.

We have established complementary research programs spanning the natural history of gastrointestinal cancer:

• Premalignant cell-state control: defining how APC-mutant cells acquire regenerative and oncofetal states and how the developmental transcription factor SOX9 recruits chromatin-remodeling machinery during tumor initiation.

• Metabolic regulation of cellular identity: determining how retinoic-acid metabolism and environmental exposures alter differentiation and establish persistent cancer-promoting states.

• Therapeutic targeting of plasticity: discovering mechanisms that force tumor differentiation or prevent cancers from transitioning into drug-resistant states.

Recent work from the laboratory and our collaborators includes a Science article describing durable epithelial metabolic memory; a JCI study defining therapy associated polyposis; work in Gastroenterology demonstrating pharmacologic induction of colorectal cancer differentiation; and emerging studies defining the molecular interaction between SOX9 and BAF chromatin-remodeling complexes during cancer initiation.

The new fellow will enter an unusually strong scientific position: substantial mechanistic groundwork, reagents, model systems, and unpublished observations are already established, while major biological questions remain

open.

We anticipate 6-18 months of overlap with experienced senior investigators, enabling intensive transfer of specialized knowledge and techniques while the incoming fellow develops ownership of the next generation of projects.

Potential projects span several interconnected areas:

• Transcription factor–chromatin remodeler biochemistry. Define the molecular principles governing interactions between developmental transcription factors such as SOX9 and BAF/SWI-SNF complexes, including protein domains, intrinsically disordered regions, complex assembly, and recruitment to chromatin.

• Programmable control of chromatin and cell state. Extend emerging approaches that repurpose transcription-factor chromatin-recruitment modules to manipulate endogenous chromatin and cellular identity.

• Retinoid metabolism and differentiation. Determine how epithelial injury rewires vitamin A/retinoic-acid metabolism, identify the metabolites and receptors responsible for altered stem-like behavior, and test whether differentiation programs can be restored during premalignancy.

• Mechanisms of cancer-cell plasticity. Define how tumor cells transition between differentiated, secretory, regenerative, and fetal-like states during oncogenic signaling and targeted therapy.

• Translational cell-state biology. Validate mechanisms using patient-derived organoids, human premalignant specimens, genetically engineered mouse models, xenografts, and other physiologically relevant systems.

Approaches in the laboratory include protein biochemistry, co-immunoprecipitation, proteomics, transcription factor biology, CRISPR engineering, degron systems, chromatin profiling, reporter systems, organoid biology, microscopy, functional genetic screens, drug perturbation, and genetically engineered mouse models, integrated with genome-scale and single-cell analyses.

Located in Boston and the surrounding communities, Dana-Farber Cancer Institute is a leader in life changing breakthroughs in cancer research and patient care. We are united in our mission of conquering cancer, HIV/AIDS, and related diseases. We strive to create an inclusive, diverse, and equitable environment where we provide compassionate and comprehensive care to patients of all backgrounds, and design programs to promote public health particularly among high-risk and underserved populations. We conduct groundbreaking research that advances treatment, we educate tomorrow's physician/researchers, and we work with amazing partners, including other Harvard Medical School-affiliated hospitals.

We seek an unusually strong and intellectually curious scientist with a Ph.D., M.D., or M.D./Ph.D. with rigorous training in experimental biology.

Strong candidates will have experience with one or more of the following:

• molecular biology and protein biochemistry;

• transcription-factor biology;

• chromatin remodeling or epigenetics;

• protein-protein interactions;

• cell signaling and cancer biology;

• CRISPR-based genetic engineering;

• organoid or stem-cell biology;

• quantitative cell biology or microscopy;

• in vivo studies

• synthetic biology

Expertise in every area is not expected. A candidate with exceptional scientific judgment, creativity, experimental rigor, and the capacity to learn quickly will be highly competitive even if their previous biological system differs from ours.

Experience with mouse models is valuable. The laboratory increasingly prioritizes investigators who can uncover mechanism and connect molecular insight to cell-state behavior.

The Sethi Laboratory sits at the interface of basic molecular biology, human cancer genetics, translational oncology, and therapeutic discovery within Dana-Farber, Harvard Medical School, and the Broad Institute. Our culture emphasizes intellectual ambition combined with collaboration.

Experimental and computational scientists work side-by-side, and projects frequently move between molecular mechanism, animal models, patient-derived systems, and human specimens.

We place particular value on scientists who are:

• deeply curious about mechanism;

• rigorous but willing to take conceptual risks;

• generous collaborators and mentors;

• comfortable learning beyond their original discipline;

• motivated to translate fundamental biology into insights that may ultimately improve prevention or treatment of human cancer.

Our long-term objective is not simply to catalog cancer-associated states. It is to determine how those states are built, why they persist, and how to control them.

The fellow will independently design and perform experiments, interpret data, develop mechanistic hypotheses, interact closely with computational and translational collaborators, prepare manuscripts and presentations, contribute to grant development, and mentor junior members of the laboratory.

Applicants should send the following to [email protected] and [email protected]:

• CV

• brief letter describing prior work, scientific interests, and potential areas of interest in the laboratory (2-page max)

• names and contact information for three references (must include PhD advisor)

Applications will be considered on a rolling basis. Start date is flexible.

At Dana-Farber Cancer Institute, we work every day to create an innovative, caring, and inclusive environment where every patient, family, and staff member feels they belong. As relentless as we are in our mission to reduce the burden of cancer for all, we are committed to having faculty and staff who offer multifaceted experiences. Cancer knows no boundaries and when it comes to hiring the most dedicated and compassionate professionals, neither do we. If working in this kind of organization inspires you, we encourage you to apply.

Dana-Farber Cancer Institute is an equal opportunity employer and affirms the right of every qualified applicant to receive consideration for employment without regard to race, color, religion, sex, gender identity or expression, national origin, sexual orientation, genetic information, disability, age, ancestry, military service, protected veteran status, or other characteristics protected by law.

EEO Poster

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Pay Transparency Statement

The hiring range is based on market pay structures, with individual salaries determined by factors such as business needs, market conditions, internal equity, and based on the candidate’s relevant experience, skills and qualifications.

For union positions, the pay range is determined by the Collective Bargaining Agreement (CBA).

$72,000.00 - $76,385.00