ASO Author Reflections: Sarcoma Organoids: Neutralizing the Word ‘‘Rare’’ in Rare Cancers

PAST

Advancements in rare cancer research have been hindered by low incidence of disease. Soft tissue sarcomas are no exception, in particular when 50+ subtypes further fragment outcomes that are dependent on adequately powered studies. Negative margin surgical resection has remained the pillar of treatment yet optimizing systemic treatments and identifying new ones has been difficult without reliable and easily reproducible preclinical research models.

Organoids are one of the fastest growing technologies in cancer research, rising in popularity due to their ability to recreate the 3D ex vivo structure of the tumor microenvironment, while maintaining the heterogeneity observed within corresponding originating tumors.^1,2 The preservation of cell interactions, signaling, and behavior within these 3D models has further increased the utility of this research tool.³ We have utilized organoids as an efficient, cost effective, and tumor agnostic platform to study rare cancers, most notably appendiceal cancer, mesothelioma, and glioblastoma,^4,5 but also more common malignancies, including lung adenocarcinoma, colorectal, and melanoma. Organoids have been shown to be robust and widely applicable research tools. Sarcomas and other rare cancers stand to benefit from routine ex vivo reconstruction and incorporation into organoid studies where otherwise, sufficiently powered clinical trials are unlikely to be performed in a reasonable timeframe.

PRESENT

We report on our experience generating patient-derived tumor organoids (PTOs) drug screen data from multiple sarcoma subtypes, including angiosarcoma, dermatofibrosarcoma protuberans (DFSP), gastrointestinal stromal tumor, leiomyosarcomas, liposarcoma, myxofibrosarcoma, and pleiomorphic sarcoma.⁶ The flexibility of this model also allowed us to study the effects of immunotherapy on PTOs enriched with patient-matched immune system components. Importantly, our workflow did not involve cell expansion before the construction of the PTOs, because we employed a surgery-based approach that directly incorporates tumor and stroma cells at peak viability into an extracellular matrix-based hydrogel. The specific approach provides three critical benefits: (1) organoid treatment results are available within 10 days from surgery that is aligned with the patient’s clinical needs; (2) incorporation of tumor specific stroma within the organoid preserves the stroma’s protective effect against treatment that otherwise would not have been accounted for in the generated treatment results; and (3) it avoids genetic drift of the cells observed through a series of expansion. The significance of this genetic drift was exhibited by sequencing of a DFSP cell line that was generated in parallel with DFSP PTOs, which demonstrated a different sequencing profile just after 8 passages. Not surprisingly the majority of PTOs were resistant to treatment, in line with current clinical observations.

FUTURE

Incorporating PTOs into routine pre-clinical use is dependent on the ability to generate data in a clinically relevant timeframe—a hallmark of this study. Continuous evolution of PTO development, imaging, and AI techniques will allow for small tissue samples and fewer cells to generate reliable results without a focus on cell expansion, which is both time-consuming and prone to genetic drift. Most importantly, preservation of viable organoids from rare tumors, such as sarcomas, will possibly allow for the first time to negate the significance of the word ‘‘rare’’ in ‘‘rare cancers,’’ by building up and prospectively maintaining over time, numbers of living rare tumors for continuous experimentation. Organoids have the potential to fill the void caused by low incidence of disease, because they can generate drug efficacy data both at the individual and cohort levels. Thus, sarcomas and other rare cancers are uniquely positioned to benefit from incorporation into organoid studies, which can generate large-scale data that has been previously lacking.