A groundbreaking cellular atlas of the mouse lemur unveils unexpected parallels with human disease and physiology, redefining the potential of this small primate as a model for medical research. In the latest comprehensive study leveraging single-cell transcriptomics, researchers have charted the cellular landscape across the entire organism of Microcebus murinus, revealing critical insights into cancer biology and adipose tissue heterogeneity that mirror complex human conditions.
At the core of this revolutionary analysis is the discovery of aggressive endometrial cancer in two elderly female lemurs, L2 and L3. This malignancy, the most common cancer of the female reproductive tract in women and a leading cause of cancer-related mortality, has rarely been modeled naturally in laboratory animals. Unlike traditional rodent models which predominantly emulate low-grade tumors, the lemur’s cancer cells exhibit molecular signatures strongly resembling high-grade, metastatic human type 2 endometrial carcinoma, presenting a crucial new avenue for studying this intractable form of cancer.
Strikingly, one of the lemurs’ metastatic tumors was found in the lung, expressing significant levels of the oxytocin receptor gene (OXTR), which is characteristically enriched in female reproductive tissues. Integration with the organism-wide atlas confirmed the tumor’s uterine origin, while histopathological examinations verified metastases not only in the lungs but also in mesenteric lymph nodes. This cellular evidence underscores the utility of organism-wide atlases to pinpoint primary tumor sites in cancers of unknown origin—a clinical challenge affecting around 2% of human cancer cases.
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At the molecular level, the uterine tumorous cells demonstrated enriched expression of canonical markers including CA125 (MUC16) and HE4 (WFDC2), widely recognized as serum biomarkers for human endometrial and ovarian cancers. Moreover, genes frequently implicated in aggressive endometrial tumorigenesis such as MYC, ERBB2 (HER2), and INHBB were upregulated, collectively mirroring the molecular profile of human type 2 tumors. The metastatic lung lesions exhibited continued expression of ERBB2 and its functional partners EGFR and EGF, suggestive of autocrine growth signaling, while simultaneously downregulating estrogen receptor (ESR1), a hallmark of advanced disease progression in humans.
Beyond oncological insights, the atlas reveals surprising aspects of lemur adipose physiology that challenge established paradigms. Mouse lemurs undergo pronounced seasonal metabolic shifts akin to hibernation states in other mammals. By profiling adipocytes across four distinct fat depots, researchers identified two main adipocyte populations differentiated by their expression of UCP1, a protein pivotal in non-shivering thermogenesis. These populations span from UCP1-high “brown-like” adipocytes characterized by enriched thermogenic regulators, to UCP1-low “white-like” adipocytes with elevated expression of classical white fat markers, blurring the conventional white-brown adipose tissue dichotomy.
Equally intriguing is the unusually low expression of leptin (LEP) in lemur adipocytes—a stark contrast to its prominent presence in human and mouse fat cells, where it modulates appetite and energy expenditure. Despite minimal leptin transcript levels, its receptor LEPR remains selectively and robustly expressed. This atypical pattern raises the possibility of highly context-dependent leptin expression or alternative regulatory mechanisms superseding canonical leptin function, potentially reflecting adaptations linked to the species’ unique seasonal physiology.
Further complicating the white-brown adipocyte distinction, both CIDEA, a prototypical brown fat marker, and RBP4, a key adipokine associated with white adipocytes, are uniformly expressed across the entire adipocyte landscape. This molecular continuum could indicate a flexible interconversion mechanism, allowing lemurs to dynamically modulate energy storage and thermogenesis in response to environmental demands, thus supporting their seasonal cycles of body weight, temperature, and metabolic rate.
Notably, no fat depot was composed solely of brown-like adipocytes; rather, each depot contained a mix or exclusively white-like cells. Gonadal fat depots displayed an enriched inflammatory gene signature, including S100A family proteins and interleukins linked to insulin resistance and metabolic stress, suggesting depot-specific immune-adipocyte interactions that could influence metabolic health especially during seasonal transitions.
The utility of the mouse lemur as a model organism expands beyond basic biology into translational research, particularly for cancers like high-grade endometrial carcinoma that lack robust animal models. Given the molecular parallels between lemur and human tumors, including shared expression of targets responsive to anti-angiogenic, anti-EGFR, and endocrine therapies, the lemur offers an invaluable in vivo system that could accelerate the development and testing of novel treatments.
Moreover, the described cellular complexity of adipose tissues provides fertile ground for probing mechanisms governing seasonal metabolic regulation in primates. Understanding adipocyte plasticity and the regulation of thermogenic programs in a natural seasonal context may illuminate strategies to tackle human metabolic disorders such as obesity and diabetes.
This comprehensive organism-wide single-cell atlas thus bridges a crucial gap between primate biology and human medicine. It not only reveals previously underappreciated physiological idiosyncrasies of a small primate but also pioneers experimental avenues to dissect disease processes in a model more closely aligned with humans than rodents.
Future work will hinge on experimental validation of these observations. Confirming the tumorigenic potential of described cell populations, dissecting the seasonal cues modulating leptin expression, and characterizing adipose tissue remodeling across seasons are essential steps toward unlocking the full research potential of Microcebus murinus.
In a broader context, this study exemplifies the power of integrative single-cell analysis to decode complex physiological and pathological states across entire organisms. It underscores how high-resolution cellular maps can identify disease origins, elucidate cell type-specific expression programs, and reveal tissue-specific adaptations with unprecedented clarity.
As the field moves forward, the mouse lemur cell atlas sets a new standard for organismal biology and primate research. It invites a reevaluation of established biological dichotomies, such as the white versus brown adipocyte classification, and opens promising investigative pathways into primate-specific disease mechanisms and therapeutic responses.
The implications extend well beyond mouse lemurs, contributing fundamentally to our understanding of evolutionary conservation and divergence in mammalian tissue organization, disease susceptibility, and physiological adaptation. The atlas thus not only enriches the scientific toolbox but also holds the promise of accelerating translational advances in human health.
Subject of Research: Mouse lemur cellular atlas; primate disease and physiology; endometrial cancer; adipose tissue biology
Article Title: Mouse lemur cell atlas informs primate genes, physiology and disease
Article References:
Ezran, C., Liu, S., Chang, S. et al. Mouse lemur cell atlas informs primate genes, physiology and disease. Nature (2025). https://doi.org/10.1038/s41586-025-09114-8
Image Credits: AI Generated
Tags: adipose tissue heterogeneity researchcancer biology insightsendometrial cancer in lemursfemale reproductive cancer parallelshigh-grade metastatic cancer modelinginnovative cancer research methodologiesMicrocebus murinus researchmouse lemur cell atlasoxytocin receptor gene expressionprimate model for human diseasesingle-cell transcriptomics studytranslational medical research
