Biomechanical regulation of chromatin states in lung cancer

The National Cancer Institute awarded Albert Einstein College of Medicine $149,190 under the Cancer Research Manpower program (CFDA 93.398) on December 18, 2025, to support research investigating biomechanical regulation of chromatin states in lung cancer.

The work examines how mechanical forces within the lung tumor microenvironment disrupt mechanosensing pathways in alveolar type 2 cells, a predicted cell-of-origin of lung adenocarcinoma. The project focuses on the interplay between CEBPA, PIEZO1, and calcium signaling in maintaining mechano-chromatin homeostasis and preventing loss of alveolar identity and disease progression. The research leverages experimental approaches to test hypotheses connecting chromatin reorganization, mechanosensory activation, and cellular fate transitions in lung cancer development.

Performance occurs in Bronx, New York, with an ultimate completion date of September 19, 2027. Albert Einstein College of Medicine, a private tax-exempt educational institution headquartered in the Bronx, serves as the recipient. The Cancer Research Manpower program provides biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research relevant to the National Cancer Program and supports awards including research training grants renewable for periods up to five years.

Abstract

The lung, a remarkable organ containing millions of air sacs or alveoli, facilitates gas exchange and serves as a barrier to environmental insults. This dynamic organ undergoes constant mechanical forces: the average human at rest takes 12-16 breaths per minute. Consequently, alveoli, comprised of alveolar type 2 (AT2) and alveolar type 1 (AT1) cells, sense and translate these mechanical cues into biological signals to maintain tissue homeostasis and alveolar identity. The nucleus, as the largest and stiffest organelle of the cell, is particularly sensitive to these physical forces. Healthy cells, through activation of the mechanosensory PIEZO1, will initiate robust responses to mechanical forces through the reorganization of the enclosed chromatin without altering cellular function. However, in lung cancer, the stiffened tumor microenvironment disrupts these essential mechanical cues, leading to the dysregulation of mechanosensing pathways. The mechanisms by which changes in the force experience of AT2 cells, a predicted cell-of-origin of lung adenocarcinoma (luad), contribute to the loss of alveolar identity, cellular diversification, and subsequent disease progression are not yet established. Our lab recently discovered that cebpa, a master regulator of alveolar cell fate, can bind the PIEZO1 locus and regulate calcium signaling. Interestingly, dysregulation of cebpa and subsequent alterations in calcium signaling contribute to accelerated alveolar fate transitions and disease progression. Additionally, we have identified that PIEZO1 is progressively downregulated in lung cancer and clinical observations associate its genetic depletion with a worse prognosis. Given the interplay between cebpa, PIEZO1, and calcium signaling, we hypothesize that these factors, in concert, are crucial for maintaining mechano-chromatin homeostasis in the lung. To test our hypothesis, we will leverage our expertise in murine modeling and epigenomic technologies to address two aims. The first aim will study how PIEZO1 and cebpa regulate chromatin remodeling events in luad cell lines following cell stretch exposure using a cell stretching device that mimics the physiological changes experienced during breathing. By subjecting cells to stretch, we can observe the resulting changes in chromatin accessibility, transcription factor activity, and nuclear architecture. The second aim will characterize the role of PIEZO1- and cebpa-dependent mechanosensing in lung cancer progression. To do so, i will take advantage of newly generated mouse models in which PIEZO1 or cebpa are depleted in combination with the activation of oncogenic mutations. My work will investigate how the loss of either gene abrogates force sensing, which can lead to increased tumor burden or severity and increased cellular diversification. The long-standing implications of my project are that restoration of homeostatic mechanotransduction pathways regulated by PIEZO1 and cebpa may ameliorate lung cancer and have broad applications to cancers of other organs with similar transitions in their mechanical microenvironments.