Selected Publications
Click here for a complete list of Mendillo Lab publications.
The HAPSTR2 retrogene buffers stress signaling and resilience in mammals
Amici DR, Cingoz H, Alasady MJ, Alhayek S, Phoumyvong CM, Sahni N, Yi SS, Mendillo ML. NATURE COMMUNICATIONS (2023)
We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1's canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.
C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways
Amici DR, Ansel DJ, Metz KA, Smith RS, Phoumyvong CM, Gayatri S, Chamera T, Edwards SL, O'Hara BP, Srivastava S, Brockway S, Takagishi SR, Cho BK, Goo YA, Kelleher NL, Ben-Sahra I, Foltz DR, Li J, Mendillo ML. PNAS (2022)
Cells utilize specialized adaptive pathways to counteract stresses imposed by environmental changes (e.g., nutrient scarcity) or quality control failures (e.g., misfolded proteins). These pathways are commonly coactivated in physiological contexts, but centralized mechanisms linking these pathways have remained elusive. Using a functional genomics approach, we mapped the constituents of and relationships between stress response pathways in human cells. We identified a conserved factor, HAPSTR1, which promotes cellular and organismal resilience under a striking diversity of stress conditions. HAPSTR1, inducible by many stressors, both cooperates with and is degraded by the E3 ligase HUWE1 in a pathway that titrates specialized proteotoxic, genotoxic, nutrient, redox, and paracrine stress response pathways. Thus, HAPSTR1 represents a central coordination mechanism for disease-relevant stress response programs.
HSF2 cooperates with HSF1 to drive a transcriptional program critical for the malignant state
Smith RS, Takagishi SR, Amici DR, Metz K, Gayatri S, Alasady MJ, Wu Y, Brockway S, Taiberg SL, Khalatyan N, Taipale M, Santagata S, Whitesell L, Lindquist S, Savas JN, Mendillo ML. SCIENCE ADVANCES (2022)
Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many noncanonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no substantial role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have notably similar chromatin occupancy and regulate a common set of genes that include both HSPs and noncanonical transcriptional targets with roles critical in supporting malignancy. Loss of either HSF1 or HSF2 results in a dysregulated response to nutrient stresses in vitro and reduced tumor progression in cancer cell line xenografts. Together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state.
A network of core and subtype-specific gene expression programs in myositis
Amici DR, Pinal-Fernandez I, Christopher-Stine L, Mammen AL, Mendillo ML. ACTA NEUROPATHOLOGICA (2021)
Myositis comprises a heterogeneous group of skeletal muscle disorders which converge on chronic muscle inflammation and weakness. Our understanding of myositis pathogenesis is limited, and many myositis patients lack effective therapies. To systematically probe the global signaling landscape in myositis muscle, we used RNA-sequencing profiles of 119 myositis and 20 control muscle biopsies to create a co-expression network comprising biological processes and disease signatures. We define dysregulated modules in clinical, MSA, and deep learning-derived myositis subsets and use network topology to evaluate putative hubs and novel components of myositis-altered pathways. Altogether, we provide a global resource to probe and contextualize differential gene expression in myositis.
See a review here that highlights our publication as one of the ten most important advances in the neuromuscular disease field in 2021.
For interactive tool go to: fireworks.mendillolab.org
FIREWORKS: a bottom-up approach to integrative coessentiality network analysis
Amici DR, Jackson JM, Truica MI, Smith RS, Abdulkadir SA, Mendillo ML. LIFE SCIENCE ALLIANCE (2020)
We created FIREWORKS, a method and interactive tool for the construction and statistical analysis of coessentiality networks centered around gene(s) provided by the user. FIREWORKS incorporates a novel bias reduction approach to reduce false discoveries, enables restriction of coessentiality analyses to custom subsets of cell lines, and integrates multiomic and drug–gene interaction datasets to investigate and target contextual gene essentiality. We demonstrate the broad utility of FIREWORKS through case vignettes investigating gene function and specialization, indirect therapeutic targeting of “undruggable” proteins, and context-specific rewiring of genetic networks.
Quantitative and multiplexed chemical-genetic phenotyping in mammalian cells with QMAP-Seq
Brockway S, Wang G, Jackson JM, Amici DR, Takagishi SR, Clutter MR, Bartom ET, Mendillo ML. NATURE COMMUNICATIONS (2020)
Here, we develop Quantitative and Multiplexed Analysis of Phenotype by Sequencing (QMAP-Seq), which leverages next-generation sequencing for pooled high-throughput chemical-genetic profiling. We apply QMAP-Seq to investigate how cellular stress response factors affect therapeutic response in cancer. QMAP-Seq reveals clinically actionable drug vulnerabilities and functional relationships involving these stress response factors, many of which are activated in cancer. Thus, QMAP-Seq provides a broadly accessible and scalable strategy for chemical-genetic profiling in mammalian cells.
The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy
Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L, Lindquist S. CELL (2014)
We examined the role of transcriptional regulator heat shock factor 1 (HSF1) in stromal cells in order to explore mechanisms of malignant progression in the tumor microenvironment. We found that HSF1 is commonly activated in cancer associated fibroblasts (CAFs). Further, the HSF1 transcriptional program in CAFs is distinct from the HSF1 program in neighboring cancer cells. These data suggest that HSF1 driven reprogramming of tumor stroma enables cancer progression and metastasis, ultimately conferring a poor prognosis.
Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State
Santagata S*, Mendillo ML*, Tang Y, Subramanian A, Perley CC, Roche SP, Wong B, Narayan R, Kwon H, Koeva M, Amon A, Golub TR, Porco JA Jr., Whitesell L, Lindquist S. SCIENCE (2013).
Our goal was to explore the relationship between metabolic pathways and cancer cell proliferation. Prior research suggests that translational flux is indicative of metabolic state and thus may affect transcriptional regulation. We found that using small molecule inhibitors to block translation globally inactivated heat shock factor 1 (HSF1), and consequently other downstream targets. Further, treatment of malignant and premalignant cells with translation initiation inhibitors impaired cell growth both in vitro and in vivo. These data suggest that HSF1 transcriptional activity may impact cancer proliferation through the modulation of energy metabolism.
HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers
Mendillo ML*, Santagata S*, Koeva M, Bell GW, Hu R, Tamimi RM, Fraenkel E, Ince TA, Whitesell L, and Lindquist S. CELL (2012).
Heat-Shock Factor 1 (HSF1), the master regulator of the heat shock response, has been shown to promote tumorigenesis, cancer cell growth, and survival. We found that HSF1 drives a unique transcriptional program in malignancy when compared to heat-shock. The HSF1 cancer program consists of many exclusively cancer-associated genes in addition to a number of heat-shock genes that are uniquely regulated in cancer. A broad range of human cancers show an active HSF1 cancer program, and further, this program is associated with a higher rate of metastasis and death.